There is a rapidly increasing need of public health significance to integrate human genetic information into analyses of population epidemiologic data to provide better understanding of biology-environment mechanisms underlying comorbidity of substance use and psychiatric disorders. In response to RFA-DA- 05-005, this R01 application requests support for 5 years to conduct coordinated analyses of NLAES, NESARC, Add Health and NHSDA/NSDUH repeated cross-sectional and/or longitudinal adolescent and adult national survey datafiles (each with different strengths and weaknesses) to provide informative results for future human-genome epidemiology (HuGE) aspects of NESARC. Race/ethnicity, immigration and acculturation, and family history, as well as gender, are conceptualized as key "low-resolution" genetic-behavioral-social (G-B-S) markers (reflecting molecular evolutionary history and recent population dynamics) to capture the interplay of genetic and environmental etiological factors. The main phenotypes are cross-sectional or longitudinal comorbidity of relatively-common substance use and psychiatric disorders or syndromes; the pleiotropy concept is applied to unrelated individuals. Add Health data with limited candidate gene information will be used to guide analyses for NESARC; when genotype information becomes available from NESARC, a portion of the phenotypic variance across race/ethnicity and individuals should be "explained away" by candidate gene main effects, epistasis, gene -environment interactions, in addition to independent environmental effects already measurable from the current NESARC datafiles. Specific analysis aims are to: 1) select phenotypes suitable for multiple-phenotype analyses by examining race/ethnicity differences on the comorbidity of two disorders that identify phenotypes that are likely to be influenced by relatively new polymorphisms or by relatively localized environmental factors or both; 2) corroborate cross-sectional phenotype selection achieved in Aim 1 from a genetic perspective; 3) delineate major gender- and race-/ethnic-specific environmental influences on the phenotypes selected in Aim 1; 4) improve polygenic measures standing-in for candidate genes for use in Aims 6), 7) and 8); 5) develop pleiotropy models of substance use abuse and psychiatric comorbidity (SAPC) to guide Aims 6), 7), and 8); 6) develop and test cross-sectional pleiotropy models for NESARC including environmental measures identified in Aim 3); 7) develop longitudinal pleiotropy models of SAPC for NESARC; 8) replicate the pleiotropy models developed in Aims 6) and 7) by replacing stand-in polygenic measures with candidate genotypes, pending on the availability of genotype data from NESARC.